19-lower alkyl-delta4-10alpha-pregnene-3,20-dione and derivatives thereof



United States Patent 3,221,012 19-LOWER ALKYL-A -a-PREGNENE-3,20-DIONE AND DERIVATIVES THEREOF Albert Bowers, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed Mar. 1, 1963, Ser. No. 262,236

Claims. (Cl. 260-23955) The present invention relates to novel cyclopentanophenanthrene compounds and to a process for the production thereof.

More particularly the present invention relates to novel 19-lower a1kyl-A -10a-pregnene-3,20-dione derivatives.

The novel compounds of the present invention are represented by the following formulae:

OZQQ In ...O R ...0 R

in the 16a,17a-position, wherein R and R each represent hydrogen or a hydrocarbon residue of up to 8 carbon atoms of straight, branched, saturated or unsaturated, cyclic or mixed aliphatic cyclic chain, or aromatic, such as methyl, ethyl, isopropyl, phenyl, toluyl, methylcyclohexyl and the like; Z represents hydrogen, methyl, chlorine or fluorine, all having a or B configurations in Formula A; W represents a double bond or a saturated linkage between C-1 and C-2; and X represents a lower alkyl group.

The acyl groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and fl-chloropropionate.

The compounds represented by the above formulae are powerful progestational agents with good oral activity. In addition they have anti-androgenic, anti-gonadotrophic and anti-estrogenic properties and are very useful in fertility control. Furthermore, they may be used in the treatment of premenstrual tension and exhibit blood cholesterol lowering and diuretic activities. When applied topically, the compounds are very useful in the treatment of acne.

The novel compounds of the present invention are prepared by the process illustrated by the following CH3 CH 0 O i .L

2 R E0 X I 0 \fm I is I (W L? (III) CH: 40 M (X): W=saturated bond (XII): W=double bond (IX): W=saturatedbo11d (XI): W=doub1e bond In the above formulae R, T, W, X and Z have the same meaning as previously described; R represents hydrogen or hydrOXyl; and R andT'together represent the group in the 16a,17 x-position, wherein R and R have the same'meaning as set forth hereinbefore.

The starting compound (I) of the present process, which is a;A -lot pregnen-19-o1-3,20-diorie derivative, is obtained according to Cross US. patent application Serial-No. 231,831 filed October 19, 1962, from the corresponding M-pregnen:19-ol-3,20-dione, by hydrogenation of the A -doub1e bond, tosylation of; the resulting allopregnan-19:0l-3,20-dione; treatment. of the obtained nen-19-al compound (111), Whichupon treatment with a lower alkyl magnesium halide, such as methyl or ethyl magnesium bromide, or a ;lower alkyl lithium compound in a solvent inert to the reagent, such as benzene, affords the corresponding 3,20-bis-cycloethylenedioxy-19-1ower alkyl-19-hydroxy-A -ot-pregnene derivative (IV). The latter reaction hydrolyzes concomitantly the l7a-acyloxy group, when it is present in the compound (III), to the corresponding 17a-hydroxyl group in compound (IV).

The aforesaid 3,20 bis-cycloethylenedioxy 19 lower alkyl-19-hydroxy-A -l0a-pregnene derivative (IV) is oxidized; preferably with chromium trioxide in pyridine, to produce the corresponding 3,20-bis-cycloethylenedioxy-19- lower alkyl=l9-keto-A -10a-pregnene derivative (V), the ketone group of which is eliminated under conventional WolE-Kishner conditions, thus afior'ding thevcorresponding 3,20-bis-cycloethylenedioxy 19 lower alkyl-A 40- pregnene derivative (VI). Treatment of the latter compound with an acid, such as hydrochloric acid, yields the corresponding l9-lower alkyl-A -lOnt-pregnene 3,20-dione (VII).

The aforesaid 3,20 bis-cycloethylenedioxy 19 lower alkyl-A -l0a-pregnene compound (VI) is treated with an organic peracid, such as monoperphthalic acid, in an inert solvent, preferably chloroform, to produce the corresponding 3,20-bis-cycloethylenedioxy-50,6a oxido 19 lower alkyl-10a-pregnane (VIII) Upon reaction of the latter 3,20-bis-cycloethylenedioxy- 5a,6oc-OXid0 compound with methyl magnesium bromide in an inert solvent such as ether or tetrahydrofuran, followed by conventional working up and treatment of the residue with a mineral acid, such as 8% sulfuric acid, and thereafter with thionylchloride in pyridine at about l0 C., for approximately 4 minutes, there is obtained the corresponding 19-lower alkyl-6fl-methyl-A -10a-pregnene-3-,20-dione (IX-z Z=B-methyl). The latter fi-methyl derivative is treatedwith an alkali metal hydroxide, such as sodium hydroxide, in a suitable solvent, such as methanol, thus affording the corresponding Got-methyl derivative (IX: Z=a-methy1),

When treating the 3,20 bis-cycloethylenedioxy 5a,6aoxido compounds (VIII) with hydrogen chloride, in a suitable organic solvent, such asethyl acetate, there are produced the corresponding 6a-chloro-19-lower. alkyl-A pregnene-3,20-dione derivatives (IX: Z=a-chlor ine).

Upon reaction of the 3,20-bis-cycloethylenedioxy-S 06-611- oxido compounds (VIII) with anhydrous hydrogen fluoride, preferably in the presence of boron trifluoride etherate, followed by treatment with hydrogen chloride, there are produced the corresponding 6a-fluoro-l9-lower alkyl- A -10ot-pregnene 3,20 dione derivatives (IX: Z==cc-fll.10- rine).

The 19-lower alkyl-A 10e-pregnene-3,20-dione derivatives (VII) are treated with ethyl orthoformate in the presence of p-toluenesulfonic acid in an inert solvent, thus affording the corresponding 19-lower alkyl-3-ethoxy- A -10a-pregnadien-2O-one derivatives which upon reaction with approximately 1 molar equivalent of- N-chlor o succinimide or another N-chloro amide or imide, in the presence of sodium acetate and acetic acid, yield the corresponding 6,8-chloro-l9-lower alkyl-A -l0ot-pregnene- 3,20-dione derivatives (IX: Z=fi-chlorine).

The aforesaid 19-lower alkyl-3-ethoxy-A -mot-pregnadien-20-one derivatives are treateclwith perchloryl fluoride in dimethylformamide, to produce the corresponding 65- fluoro-19-lower alkyl-A -10u-pregnene-3,20-dione derivatives (IX: Z=[3-fluorine).

The oat-halo compounds of the present invention (IX: Z -e-halogen) .may. also be obtained by treatment of the corresponding 6fi-halo compounds (IX: Z=/3-halogen) with hydrogen chloride in acetic acid.

The 19-lower alkyl-A 10ot-pregnene-3,2O-dione derivatives (IX) are treated with 2,3-dichloro-5,6-dicyan0-1,4 benzoquinone in an inert solvent, such as dioxane, preferably at'reflux temperature for a period of time of approximately 10 hours. to, produce the corresponding 19-lower alkyl-A -10u-pregnadiene-3,20-dione compounds (XI);

The. 19-10wer alky1-A -10a-pregnene-3,20-dione derivatives (IX) upon treatment with ethyl orthoformate in an inert solvent and in-the presence of p-toluenesulfonic acid' furnish thecorresponding 19-lower alkyl 3 ethoxy-A IOa-pregnadiene derivatives, which are treated with approximately 1 molar equivalent of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, in the presence of a catalytic amount of acid and in aninert solvent, to give the corresponding 19-lower alkyl-A -1Oa-pregnadiene-3,20 dione derivatives (X).

The latter A -compounds may be convertedinto the corresponding N -derivatives (XII) by further treat ment with 2,3-dichloro 5,6 dicyano 1,4-benzoquinone under, the conditions specified hereinbefore for the production of the Ai -derivatives (XI).

Thecornpounds of the present invention having a l7a -ketonide grouping, yield the corresponding 16u,17a,

diols, ,by, conventional treatment witha strong acid such as formic acid. The obtained diols, upon conventional esterification in pyridine with an acylating agent, as for example, acetic anhydride or caproic anhydride, afford the corresponding 16-acylates.

The latter 16a,17a-diols upon conventional condensation with a ketone or aldehyde, such as benzaldehyde, acetophenone, methyl ethyl ketone, acetone, and the like, in the presence of an acid, yield the corresponding 16a, l7a-methylenedioxy derivatives, wherein the substituents in the methylenedioxy group may be different from those of the previously hydrolyzed ketonide grouping.

The compounds of the present invention having a hydroxyl group at C-17a, may be acylated by conventional treatment with an acylating agent, such as an anhydride derived from a hydrocarbon carboxylic acid of the type described hereinbefore, in the presence of p-toluenesulfonic acid, to produce the corresponding 17a-esters.

The following examples serve to illustrate the present invention, but are not intended to limit the scope thereof:

Example I A mixture of 5 g. of A -a-pregnen-19-ol-3,20-dione (Cpd. No. 1) (Cross, U.S. pat. appl. Ser. No. 231,831 filed Oct. 19, 1962) 150 cc. of anhydrous benzene, 60 cc. of ethyleneglycol distilled over sodium hydroxide and 800 mg. of p-toluenesulfonic acid monohydrate was refluxed for 12 hours with the use of an adapter for the continuous removal of the water formed during the reaction. Aque ous sodium bicarbonate solution was added to the cooled mixture and the organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from acetone-hexane to give 3,20 bis cycloethylenedioxy-A 10a-pregnen-l9-ol (Cpd. No. 8).

Following exactly the same procedure, the starting compounds listed hereinafter under A (obtained according to the aforesaid patent application) were converted, respectively into the corresponding compounds set forth under B.

Following exactly the same procedure, the compounds Nos. 9 to 14, inclusive, were respectively transformed into:

Example IV A solution of 5 g. of 3,20-bis-cycloethylenedioxy-M- 10a-pregnen-19-al (Cpd. No. 15) in 250 cc. of thiophene free benzene was treated with 27.5 cc. of -4 N methyl magnesium bromide in ether and the mixture refluxed with the exclusion of moisture for 3 hours. The cooled mixture was cautiously treated with excess aqueous ammonium chloride solution and the product isolated by ethyl acetate extraction. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness.

Recrystallization from methylene chloride-hexane afforded 3,20 bis-cycloethylenedioxy l9-methyl-A -10apregnen-19-ol (Cpd. No. 22).

Following the same procedure the compounds Nos. 16 to 21, inclusive, were converted respectively into:

Cpd. No.:

23. 3,20 bis cycloethylenedioxy-l6a,19-dimethyl- A -10a-pregnen-19-ol.

Cpd. A

16a-methyl-A 10a-pregnen-19-ol-3,

20-dione. 16B- ethyl-A I0a-pregnen-19-ol-3,

20-dione.

16or,17ei-isopropylidenedioxy-A' 10u-pregnen-19-0L3,20-dione.

pregnen-lQ-ol. A -10m-pregnene-17a-19-di0l-3,20

die e n 16a-methyl-A -1Oa-pregnene-17 or,

19-di0l-3,20-dione.

3,20-bls-cyeloethylenedloxy-l6amethyl-A -10a-pregnen-19-ol.

3,20-bis-cycloethylenedioxy-lfiflmethyl-N-lOa-pregnen-19-ol.

3,20-bis-cycloethylenedioxy-lfia,

17a-isopropylidenedloxy-M-10a- 3,20-bis-cycloethylenedioxy-A 1Oa-pregnene-17ad9-d1ol 3,20-his-cycloethylenedioxy-ltiag eghyl-h -10a-pregnene-17a,19-

Example II l6 8-methy1-A -IOa-pregnene 170:,19 diol 3,20-dione (Cpd. No. 7), obtained in accordance with my copending U.S. pat. appl. Ser. No. 231,831, filed October 19, 1962, was treated following the above procedure, thus furnishing 3,20 bis-cycloethylenedioxy 16/3 methyl-A 10a-pregnene-17a,19-diol (Cpd. No. 14).

Example III A solution of 6 g. of 3,20-his-cycloethylenedioxy-A 10a-pregnen-19-ol (Cpd. No. 8) in 120 cc. of pyridine was added to a mixture of 6 g. of chromic trioxide in 120 cc. of pyridine. The reaction mixture was kept at room temperature overnight. It was then diluted with ethyl acetate, filtered through celite and the filtrate washed well with water, dried and evaporated to dryness. Crystallization from acetone-hexane alforded 3,20-bis-cycloethylenedioxy-A -10a-pregnen-19-al (Cpd. No. 15).

Example V 3,20 bis cycloethylenedioxy-A -1Oa-pregnen-19-ol (Cpd. No. 15) was treated in accordance with Example IV, except that methyl magnesium bromide was substituted by ethyl magnesium bromide, thus yielding 3,20-biscycloethylenedioxy-19-ethyl-A -10a-pregnen-19-o1 (Cpd;

The compounds Nos. 16 to 21, inclusive, were treated by the same procedure, thus affording respectively:

Cpd. N0.:

30. 3,20 bis cycloethylenedioxy-16a-methyl-19- ethyl-A -10a-pregnen-19-ol.

31. 3,20 bis cycloethylenedioxy-16p-methyl-19- ethyl-M-lOa-pregnen-19-ol.

'32. 3,20 bis-cycloethylenedioxyl6a,17a-isopropyllidenedioxy-19-ethyl-A -10a-pregnen-19-o1.

33. 3,20 bis cycloethylenedioxy-19-ethyl-A -10apregnene-17a,l9-diol.

34. 3,20 bis cycloethylenedioxy-16a-methyl-19- ethyl-A 40a-pregnen-l7u-l9-diol.

35. 3,20 bis cycloethylenedioxy-16B-methyl-19- ethyl-A 40u-pregnene-17a,19-diol.

Example VI A solution of 6 g. of 3,20-bis-cycloethylenedioxy-19- methyl-A -10a-pregnen-19-ol (Cpd. No. 22) in 120 cc. of pyridine was added to a mixture of 6 g. of chromic trioxide in 120 cc. of pyridine. The reaction mixture was kept at room temperature overnight. It was then diluted with ethyl acetate, filtered through celite and the filtrate washed well with water, dried and evaporated to dryness. Crystallization from acetone-hexane afforded 3,20 bis-cycloethylenedioxy-19-methyl-A -wot-pregnanc- 19-one (Cpd. No. 36). Following the same procedure the compounds Nos. 23 to 35, inclusive, were converted respectively into:

Cpd. N0.:

37. 3,20-bis-cycloethylenedioxy-16a,19-dimethyl- A -10u-pregnen-19-one.

38. 3,20-bis-cycloethylenedioxy-165,l9-dimethyl-A 10a-pregnen-19-one. v

39. 3,20-bis-cycloethylenedioxy-16a,17a-isopropylidene-dioxy-19-methyl-A -IOu-pregnen-19-one.

40. 3,20-bis-cycloethylenedioxy-19-methyl-A -10apregnen-17ot-ol-19-one.

41. 3,20-bis-cycloethylenedioxy-16a,l9-dimethyl-A 10a-pregnen-17u-ol-19-one.

42. 3,20-bis-cycloethylenedioxy-16B,19-dimethyl-A 10a-pregnen-17a-ol-19-one.

43. 3,20-bis-cycloethylenedioxy-19-ethyl-A -10apregnen- 19-one.

44. 3,20-bis-cycloethylenedioxy-16a-methyl-19-ethyl- A -10u-pregnen-19-one.

45. 3,20-bis-cycloethylenedioxy-16/3-methyl-l9-ethyl- A -lu-pregnen-l9-one.

46. 3,20-bis-cycloethylenedioxy-16a,17oc-isopropylidene-dioxy-19-ethyl-A -a-pregnen-19-one.

47. 3,20-bis-cycloethylenedioxy-l9-ethyl-A -10a pregnen-17a-ol-l9-0ne.

.48. 3,20-bis-cycloethylenedioxy-16a-methyl-19- ethyl-A -10a-pregnen-17a-ol-19-one.

49. 3,20-bis-cycloethylenedioxy-16,8-methyl-19- ethyl-A -10a-pregnen-17a-ol-19-one.

Example VII A mixture of 1 g. of 3,20-biscycloetl1ylene,dioxy-19- methyl-A -10u-pregnen 19-one (Cpd. No. 36), 2 g. of hydrazine hydrate, 1.2 g. of potassium hydroxide, 1.2 cc. of water and 1.2 cc. of diethylene glycol was heated under reflux for 45 minutes. It was then heated in an open flask until the temperature of the reaction mixture reached 200 C., a reflux condenser was attached, and refluxing was continued for a further 2 hours. The solution was cooled, water added and the product isolated by extraction with ether. Recrystallization of the residue obtained after evaporation of the solvent from acetone-hexane afforded 3,20 bis-cycloethylenedioxy-19- methyl-A -10m-pregnene (Cpd. No. 50).

The compounds Nos. 37 to 49, inclusive, were treated by the above procedure, thus furnishing respectively:

Cpd. N0.:

5 1. 3,20-bis-cycloethylenedioxy-16u,19-dimethyl-A IOa-pregnene.

52. 3 ,20-bis-cycloethylenedioxy- 1 6 8, 19-dimethyl-A 10ot-pregnene.

5 3. 3,20-bis-cycloethylenedioxy-16a,17m-isopropylidene-dioxy-19-methyl-A -10ot-pregnene.

54. 3,20-bis-cycloethylenedioxy-19-methy1-A -10apregnen-l7ct-ol.

55. 3,20-bis-cycloethylenedioxy-16a,19-dimethyl-A l0u-pregnen-17aol.

56. 3,2O-bis-cycloethylenedioxy-16;8,19-dimethyl-A 10a-pregnen-17a-ol.

57. 3,20-bis-cycloethylenedioxy-19-ethyl-A -10upregnene.

58. 3,20-bis-cycloethylenedioxy-16a-methyl-19-ethyl- A -10a-pregnene.

59. 3,20-bis-cycloethylenedioxy-16/3-rnethyl-19- ethyl-M-lOa-pregnene.

60. 3,20-bis-cycloethylenedioxy-16u,l7a-is0propylidene-dioxy-19-ethyl-A -loot-pregnene.

61. 3,20-bis-cycloethylenedioxy-19-ethyl-A -10apregnen-17a-ol.

62. 3,20-bis-cycloethylenedioxy-16a-methyl-19-ethyl- A -10a-pregnen-17a-ol.

63. 3,20-bis-cycloethylenedioxy-16,8-methy1-19-ethyl- A -10a-pregnen-l7a-ol.

Example VIII A solution of 500 mg. of 3,20-bis-cycloethylenedioxy- 19-methyl-A -10u-pregnene (Cpd. No. 50) in 25 cc. of acetone was treated with 0.1 cc. of concentrated hydrochloric acid and the mixture kept at room temperature overnight. It was then poured into water, extracted with methylene chloride and the organic extract washed with Water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone hexane gave 19-methyl-A -l0a-pregnene-3,20-dione (Cpd.

Following the same procedure, the compounds Nos. 51 to 63, inclusive, were converted respectively into:

Example IX A solution of 2.5 g. of 3,20-bis-cycloethylenedioxy-19- methy1-A -10a-pregnene (Cpd. No. 50) in cc. of chloroform was cooled to 0 C. and mixed with 1.1 molar equivalents of monop'erphthalic acid in ether solution. The mixture was kept at room temperature for 20 hours, diluted with water, the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hex- 9 ane gave 3,20- bis cycloethylenedioxy l9-methyl-5a,6 xoxido-l a-pregnane (Cpd. No. 78).

The compounds Nos. 51 to 63, inclusive, were treated by the above procedure, thus furnishing respectively Example X To a solution of 40 cc. of 4 N methyl magnesium bromide in ether was added, with stirring, a solution of 2 g. of 3,20-bis-cycloethylenedioxy-19-methyl-5u,6a-oxido-10apregnane (Cpd. No. 78), in 60 cc. of dry tetrahydrofuran and the stirred mixture heated under reflux for 30 minutes. The condenser was then replaced by a calcium chloride tube, the ether allowed to boil oil and when the internal temperature reached 54 C., the condenser was readapted and the mixture refluxed for an additional 4 hours. 400 cc. of a saturated solution of ammonium chloride was added slowly to the cooled mixture which was then stirred for 15 minutes before transfer to a separatoryfunnel. It was then diluted with ethyl acetate, the organic layer was s'eparated,,dried and evaporated to dryness, thus afiordiug a solid residue.

A solution of this residue in 70 cc. of methanol and 7 cc. of 8% aqueous sulfuric acid was refluxed for 40 minutes. It was then neutralized with saturated sodium carbonate solution, concentrated toca. 20 cc. in vacuo and poured into water. The formed precipitate was filtered ofi, washed thoroughly with water and air dried.

A solution of the dry precipitate in 7 cc. of dry pyridine was cooled to 10 0, treated with 0.4 cc. of thionyl chloride and the mixture allowed to stand for v4 minutes at this temperature. Ice-water was added and the crystalline precipitate was filtered, washed and dried, yielding 6 3,19 dimethyl A 10a pregnene 3,20- dione (Cpd. No. 92).

Followingth-e same procedure, the compounds Nos. 79 to 91, inclusive, were converted respectively into:

Cpd. No.:

93. 6B,16a,19-trimethyl-A -10u-pregnene-3,20-dione.

94. 6,63,16,13,19-trimethyl-A -l0a-pregnene-3,2O dione.

95. 16a,17a-isopropylidenedioxy-6li,19-dimethyl-A 10ot-pregnene-3,20-dione.

96. 61?,1;9-dimethyl-A -10a-pregnen-17a-ol-3,2O

dione.

97. 6 3,16a,19-trimethyl-A -IOa-pregnen-17a-ol- 3,20-dione.

98. 6B,16B,l9-trimethyl-A -l0a-pregnen-l7a-ol- 3,20-dione.

10 Cpd. No.:

99. 6 3-methyl-19-ethyl-A -10a-pregnene-3,20-dione.

100. 6,8,16a-dimethyl-19-ethyl-A -10a-pregnene- 3,20-dione.

l0 1 6e, 16B-dimethy1-19-ethyl-A -loot-pregnene- 3,20-dione.

102. 16a,17a-isopropylidenedioxy-6 3-methyl-19- ethyl-A -10a-pregnene-3,20-dione.

1103. 6 8-methyl-l 9-ethyl-A -Illa-pregnen-1701-01- 3,20-dione.

i104. 6/3,loot-dimethyl-19-ethyl-A -10a-pregnen-17aol-3,20-dione.

105. 6 8,l6 3-dimethyl-l9-ethyl-d -l0o -pregnen-l7aol-3,20-dione.

Example. XI

1 g. of 65,19 dimethyl-A 400 pregnene 3,20 dione (Cpd. No. 92) was dissolved in 20 cc. of methanol containing 0.2 g. of sodium hydroxide and the mixture was kept for one and a half hours at room temperature, then poured into water and extracted with methylene chloride. Evaporation of the methylene chloride solution and crystallization of the residue from acetone-hexane yielded 6a,19 dimethyl-A -10a-pregnene 3,20 dione (Cpd. No.

Following the same procedure, the compounds Nos. 93 to 105,. inclusive, were convertedrespectively into:

Cpd. No.:

107. 6a,16a,19-trimethyl-A -1Oa pregnene-3,2O-

dione.

108. 60a, 1 6 6, 19-trirnethy1-A -1 Out-pregnene- 3,20-di0ne.

109. 16a,17a-isopropylidenedioxy-6a,19- dimethyl-A -10a-pregnene-3,20-dione.

110. 6a,19-dimethyl-A -IOu-pregnene-17a-ol- 3,20-dione.

11 1. 6a,16a,19-trirnethyl-A -1Oat-pregnen- 17a-ol-3,20-dione.

112. 6a,16/3,19-trimethyl-A -10a-pregnen-17aol-3,20-dione.

113. 6a-methyl-19-ethyl-A -10a-pregnene- 3,20-dione.

114. 6a,16a-dimethyl-19-ethyl-A -10a-pregnene- 3,20-dione.

115. 6a,1'6,6-dimethy1-19-ethyl-A -loot-pregnene- 3,20-dione.

116. 16a,17a-A-isopropy1idenedi0Xy-6a-methyl- 19-ethyl-A -l0u-pregnene-3,20-dione.

117. 6a-methyl-19-ethy1-A -10a-pregnene-17aol-3,20-dione.

118. 6a,16a-dimethyl-19-ethyl-A -10a-pregnen- 17a-ol-3,20-dione.

119. 6a,16fidimethyl-19-ethyl-A -1Out-pregnen- 170t-Ol-3,20-dl011.

Example XII Into a suspension of 1 g. of 3,20-bis-cycloethylenedioxy- 19-methyl-5u,6a-oxido-IOa-pregnane (Cpd No. 78) in 35 cc. of glacial acetic acid, was passed a slow stream'of dry hydrogen chloride, after 10 minutes all the solidmaterial was dissolved. .Thegas was passed through the reaction mixture for a total of 5 hours. The solution was concentrated to about one-third its initial volume by distillation under reduced pressure at 35 C., then it was poured into ice-water. The precipitate formed was collected, washed with water to neutrality and dried. Recrystallization from methylene chloride afl'orded 6a-chloro-19-methyl-A -l0a-pregnene-3,20-dione (Cpd. No.

Following the same procedure, the compounds Nos. 79 to 91, inclusive, were converted respectively into:

Cpd. No.:

121. 6m-chloro-16a,19-dimethyl-A -10apregnene-3,20-dione. 122. 6a-chloro-1618,19-dimethyl-A -1Oapregnene-3,20-dione.

11 Cpd. No.:

123. 6u-ch1oro-16a,17a-isopropylidenedioxy-19- methyl-A -10u-pregnene-3,20-dione.

124. 6u-chloro-19-methyl-A -lOot-pregnen-17aol-3,20-dione.

125. 6a-ch1oro-16a,19-dimethyl-A -10apregnen-17a-ol-3,20-dione.

126. 6u-chloro-16,B,19-dimethyl-A -10apregnene-17u-ol-3 ,20-dione.

127. 6u-chloro-19-A -10u-pregnene- 3,20-dione.

128. 6a-chloro-16u-methyl-19-ethyl-A -10apregnene-3,20-dione.

129. 6u-chloro-16/3-methyl-19-ethyl-A -10 x- 'pregnene-3 ,ZO-dione.

130. 6a-chloro-16a,17a-isopropylidenedioxy-19- ethyl-A -10a-pregnene-3,20-dione.

131. Goa-chloro-19-ethy1-A -10a-pregnen- -17a-ol-3,20-dione.

132. 6a-chloro-16u-methyl-19-ethyl-A -10apregnen-17a-ol-3,20-dione.

133. 6oc-chloro-16fl-methyl-19-ethyl-A -10apregnen-17a-ol-3,20-dione.

Example XIII 2.8 cc. of boron tn'fluoride etherate was slowly added with stir-ring to 220 mg. of anhydrous hydrogen fluoride cooled in an acetone-Dry Ice bath.

To a solution of 1 g. of compound N0. 78 in 10 cc. of a mixture of equal parts of benzene. and ether was added 1.3 cc. of the fiuoroboric acid reagent. The mixture was kept for 3 hours at room temperature, then washed four times with water, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was suspended in 40 cc. of ethyl acetate and there Was passed a slow stream of dry hydrochloric acid. The gas was passed through the reaction mixture for a total of 5 hours. The solution was then washed abundantly with water, dried and evaporated to dryness. The residue was washed with water to neutrality and dried. Recrystallization from methylene chloride-hexane afforded 6a fluoro-19-methyl-A -u-pregnene-3,20-dione (Cpd. No. 134).

Following the same procedure, the compounds Nos. 79 to 91, inclusive, were converted respectively into:

Cpd. No.:

135. 6a-fluoro-16u,19-dimethyl-A -10apregnene-3,20-dione.

136. 6a-fluoro-16fi,19-dimethyl A -10apregnene-3,20-dione.

137. 6a-fluoro-16a,17a-isopropylidenedioxy-19- methyl-A -10a-pregnene-3,20-dione.

138. 6ot-fluoro-19-methyl-A -IOa-pregnen- 17a-ol3,20-dione.

139. 6a-fluoro-16u,19-dimethyl-A -10apregnene-17a-ol-3,20-dione.

140. 6a-fluoro-16B,19-dimethy1-A -10apregnene17a-ol-3,20-dione.

141. 6u-fluoro-19-ethyl-A -10u-pregnene- 3,20-dione.

142. 6a-fluoro-16a-methyl-19-ethyl-A -10apregnene-3,20-dione.

143. 6a-fluoro-16;3-methyl-19-ethyl-A -10apregnene-3,20-dione.

145. 6a-fluoro-19-ethyl-A -10a-pregnen-17uol-3,20-dione.

146. 6a-fiuoro-16a-methyl-l9-ethyl-A -10apregnen-l 7oc-01-3 ,ZO-dione.

147. 6o -fluoro-16 8-methyl-19-ethyl-A -10apregnen-17a-ol-3,20-dione.

12 Example XIV A suspension of 1 g. of 19-methyl-A -1Oaregnene- 3,20-dione (Cpd. No. 64) in 7.5 cc. of anhydrous peroxidefree dioxane was treated with 1.2 cc. of freshly distilled ethyl orthoformate and 0.8 g. of p-t-oluene-sulfonic acid. The mixture was stirred at room temperature for 15 minutes and the resulting solution let stand for 30 minutes further. 0.8 cc. of pyridine were added and then water. The formed precipitate was collected by filtration, water washed and air dried. Recrystallization from acetonehexane afiorded 3-ethoxy-19-methyl-A -lOu-pregnadien- 20-one (Cpd. No. 148).

The compounds Nos. 65 to 77, inclusive, were treated following the above procedure, thus producing respectively:

Cpd. No.:

149. 3-ethoxy-16a,19-din1ethyl-A -IOaregnadien- 20-one.

150. 3-ethoxy-1613,19-dimethyl-A -IOaregnadien- 20-one.

151. 3-ethoxy-16a-17a-isopropylidenedioxy-19- methyl-A -l0a-pregnadien-20-one.

152. 3-ethoxy-19-methy1-A -IOu-pregnadien-lhol-20-one.

153. 3-ethoxy-160:,19-dimethyl-A -IOa-pregnadien- 17a-ol-20-one.

154. 3-ethoxy-16B,19-dimethyl-A -IOa-pregnadien- 17a-ol-20-one.

155. 3-ethoxy-19-ethy1-A -IOa-pregnadien-ZO-One.

156. 3-ethoxy-16a-methyl-19-ethyl-A -10a-pregnadien-20-one.

15 7. 3-ethoxy- 1 fifi-methyl-l9-ethyl-A 1 Oat-pregnadien-20-one.

158. 3*ethoxy-16a,l7u-isopropylidenedioxy-19 ethyl- A -IOa-pregnadien-ZO-One.

159. 3-ethoxy-19-ethyl-A -1Ou-pregnadien-17a-ol- 20-one.

160. 3-ethoxy-16u-methyl-19-ethyl-A -10a-pregnadien-17a-0l2O-one.

161. 3-ethoxy-16fi-methy1-19-ethyl-A -IOa-pregnadien-17a-ol-20-0ne.

Example XV A mixture of 5 g. of 3-eth0xy-19-methy1-A -1Out-pregnadien-20one (Cpd. No. 148), 2 g. of anhydrous sodium acetate and cc. of acetone was treated with 32 cc. of water and the solution was cooled to a temperature between 0 and 5 C. There was then added 1.1 molar equivalents of N-chloro-succinimide and 2 cc. of glacial acetic acid and the mixture was stirred between 0 and 5 C. for 30 minutes. It was then diluted with water, kept overnight at 0 C. and the precipitate formed was collected, washed with water, dried under vacuum and recrystallized from acetone thus giving 6/8-chloro-19-methy1- A -10a-pregnene-3,20-di0ne (Cpd. No. 162).

Following the same procedure, the compounds Nos. 149 to 161, inclusive, were converted respectively into:

Cpd. No.:

163. 6,8-chloro-16a,19-dimethyl-A IOa-pregnene- 3,20-dione.

164. GB-chloro-16fi,l9-dimethy1-A -1Oaregnene- 3,20-dione.

165. 613-chloro-16a,17a-isopropylidenedioxy-19- 1 methyl-A -10a-pregnene-3,20-dione.

166. 6fi-chloro-19-methyl-A -10a-pregnen-17a-ol- 3,20-dione.

167. 6fl-chloro-16u,19-dimethyl-A -IOa-pregnen- 17a-ol-3,20-dione.

168. 6fi-chloro-16,8,19-dimethyl-A -IOu-pregnen- 169. 6 3-chloro-l9-ethyl-A -10a-pregnene-3,20-dione.

1'70. 6p-chl0ro-16a-methy1-19-ethyl-A -10a-pregnene-3,20-dione.

Example XVI 1 g. of 3-ethoxy-19-methyl-A -IOa-pregnadien-ZO-One (Cpd. No. 148) was dissolved in 25 cc. of dimethylformamide. The solution was cooled to C. and a stream of perchloryl fluoride was passed for minutes; the solution was allowed to come slowly to 20 C.; it was then poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, then with water to neutrality, dried over anhydrous sodium sulfate, and evaporated to dryness. By chromatography over washed alumina there was obtained 6fl-fluoro-19-methyl-A -10a-pregnene-3,20dione (Cpd. No. 176).

Following the same procedure, the compounds Nos. 149 to 161, inclusive, were converted respectively into:

Cpd. No.:

177. 6B-fluoro-16a,19-dimethyl-A -10a-pregnene- 3,20-dione.

178. 6,6-fiuoro-16B,19-dimethyl-A -10a-pregnene- 3,20-dione.

179. 6fi-fluoro-16a,17a-isopropy1idenedioxy-19- methyl-A -10a-pregnene-3,20-dione.

180. 6,8-fiuoro-19-methy1-A -10a-pregnen-17a-ol- 3,20-dione.

181. G/B-fluoro-16a,19-dimethyl-A -10a-pregnen- 17a-Ol3,20-dl011.

183. 6,8-fluoro-19-ethyl-A -10apregnene-3,20-dione 184. 6/3-fluoro-l6a-methyl-19-ethyl-A -10a-pregnene- 3,20-dione 185 6fi-fluoro-16fl-methyl-19-ethy1-A -10a-pregnene- 3,20-dione 186. 6/3-fluoro-16a,17a-isopropylidenedioxy-19-ethyl- A -10a-pregnene-3,20-dione 187. 6 8-fluoro 19-ethyl-A -10a-pregnen-17oc-ol-3,20-

dione 188. 6/3 fluoro-l6a-methyl-19-ethyl-A -10a-pregnen- 17ot-O1-3,20di0116 189. 6,8 fiuoro-l6B-methy1-19-ethyl-A -10a-pregnen- 17a-ol-3,20-dione Example XVII A solution of 1 g. of 3-ethoxy-19-methyl-A -10a-pregnadien-ZO-one (Cpd. N0. 148) in 20 cc. of tetrahydrofuran was cooled to 0 C. and there were added 1.05 molar equivalents of 2,3-dichloro-5,G-dicyano-1,4-benzoquinone and 100 mg. of p-toluenesulfonic acid. The resulting mixture was further stirred at 0 C. for 30 minutes. The precipitated hydroquinone was filtered oil and 100 cc. of methylene chloride were added to the filtrate. The organic solution was washed with 5% aqueous sodium hydroxide solution until. the washings were colorless, then with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 19-methyl-A -10a-pregnadiene-3,20-dione (Cpd. No. 190).

Following the same procedure, the compounds Nos. 149 to 161, inclusive, were converted respectively into:

Cpd. No.: I 191. 160:,19 dimethyl-A -10a-pregnadiene-3,2O-d1- one 14 Cpd. No.2

192. 165,19-dimethyl-A -10a-pregnadiene-3,20-dione 193. 161X,17OL-ISOPI'OPY1ld6D6dlOXY-19-H1thyl-A -10Ctpregnadiene-3,20-dione 194. 19 methyl-A -10a-pregnadien-17a-ol-3,20-dione 195. 160:,19 dimethyl-A -10u-pregnadien-17a-ol- 3,20-dione 196. 1618,19 dimethyl-A -10a-pregnadien-17a-o1- 3,20-dione 197. 19-ethylA -1Oa-pregnadiene-S,20-dione 198. 16a-methyl-9-ethyl-A -10a-pregnadiene-3,20-dione 199. 1613 methyl-1'9-ethy1-A -10a-pregnadiene-3,20-

dione 200. 16a,17u isopropylidenedioxy-19-ethyl-A -10ozpregnadiene-3,20-dione 201. 19-ethyl-A -1Oa-pregnadien-17a-ol-3,20-dione 202. 16or-methyl-19-ethyl-A -10a-pregnadien-17a-0l- 3,20-dione 203; 16fi-methyl-19-ethyl-A -10a-pregnadien17a-o1- 3,20-dione Example XVIII 6ot-chloro-19-methyl-A -10a-pregnene-3,20-dione (Cpd. No. was successively treated in accordance with Examples XIV and XVII, thus yielding as final product 6-chloro-19-methyl-A -10a-pregnadiene-3,20dione (Cpd. No. 204).

Following the same procedure, the compounds Nos. 121 to 133, inclusive, were converted respectively into:

Cpd. No.:

205. 6-chloro-16a,19-dimethyl-A -1Oa-pIegnadiene- 3,20-dione 206. 6-chloro-16,8,19-dimethyl-A -IOaregnadiene- 3,20-dione 207. 6 chloro-16a,17a-isopropy1idenedioxy-19-methyl-A -10a-pregnadiene-3,20-dione 208. 6-chloro-19-methyl-A -10a-pregnadien-17a-ol- 3,20-dione 209. 6 chloro-16a,19-dimethyl-A -10a-pregnadien- 17zx-0l-3,20-di0116 210. 6 chloro-l6B,19-dimethyl-A -IOa-pregnadien- 17a-ol-3,20-dione 211. 6 chloro-19-ethyl-A -10a-pregnadiene-3,20-dione 212. 6-chloro-1 6a-methyl-19-ethyl-A -1Oa-pIegnadiene-3,20-dione 213. 6-chloro-16B-methyl-19-ethyl-A -10a-pregnadiene-3,20dione 214. 6 chloro-l6a,17a-isopropylidenedioxy-19-ethyl- A 40u-pregnadiene-3,20-dione 215. 6 chloro-19-ethyl-A -10a-pregnadien-17a-ol- 3,20-dione 216. 6-chloro-16a-methy1-19-ethyl-A -10u-pregnadien-17a-ol-3,20-dione 217. 6-chloro-1613-methyl-19-ethyl-A -IOaregnadien-17a-ol-3,20-dione Example XIX The final compounds of Examples XI and XIII were treated successively in accordance with Examples XIV and XVII, thus affording as final products the corresponding A -10u-pregnadiene-derivatives.

Example XX A mixture of 500 mg. of 19-methyl-A -1Oaregnene- 3,20-dione (Cpd. No. 64), 10 cc. of dioxane and 350 mg. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was refluxed for 10 hours. It was then cooled, the 2,3-dichloro-5,6- dicyano-1,4-benzohydroquinone formed during the reaction filtered off, and the filtrate evaporated to dryness. The residue was dissolved in acetone and filtered through 10 g. of alumina. Crystallization from acetone-hexane 15 gave 19-methy1-A -10a-pregnadiene-3,2O-dione (Cpd. No. 218).

Following the same procedures, the compounds Nos. 65 to 77, inclusive, were converted respectively into:

Cpd. No.:

- 219.16a,19-dimethyl-A -1Oa-pregnadiene-S,ZO-dione 220. 16B,19-dimethyl-A -10a-pregnadiene-3,20-dione 221. 16a,l7a-isopropylidenedioxy-19-methylA -10apregnadiene-3,20-dione 222. 19-methyl-A -10a-pregnadien-17a-ol-3,ZO-dione 223. 16a,19 dirnethyl A -10a-pregnadien-17a-ol- 3,20-dione 224. 1618,19 dimethyl-A -10a-pregnadien-17a-ol- 3,20-dione 225. 19-ethyl-A -la-pregnadien-3,20-dione 226. 16a-methyl-19ethyl-A -a-pregnadiene-3,20-

dione 227. 16p-methy1-19-ethyl-A -10a-pregnadiene-3,20-

dione 228. 16u,171x isopropylidenedioxy-19-ethyl-A -10apregnadiene-3,20-dione 229. 19-ethyl-A -1Oat-pregnadien-l7u-ol-3,20-dione 230. 16a-methy1-19-ethyl-A -10u-pregnadien-17a-ol- 3,20-dione 231. 16,8-methyl-19-ethy1-A -10a-pregnadien-17aol-3,20-dione Example XXI The compounds Nos. 92 to 105, inclusive, were treated in accordance with Example XX, thus producing respectively:

Cpd. No.:

232. 6B,19-dimethy1-A -10a-pregnadiene-3,ZO-dione 233. 6B,16a,19-trimethy1-A -wot-pregnadiene- 3,20-dione 234. 6B,16B,19-trimethyl-A -loot-pregnadiene- 3,20-dione 235. 16a,17a-isopropylidenedioxy-6 3,19-dirnethyl- A -10a-pregnadiene-3,20-dione 236. 613,19-dirnethyl-A -l0a-pregnadien-l7a-ol- 3,20-dione 237. 6B,16a,19-trimethy1-A -10a-pregnadien-17aol-3,20-dione 238. 6B,1618,19-trimethy1-A -10a-pregnadien-17aol-3,20-dione 239. 6B-methy1-19-ethy1-A -IDOL-pregnadiene- 3,20-dione 240. 613,16a-dimethyl-19-ethy1-A 10apregnadiene-3,20-dione 241. 613,16B-dimethyl-19-ethy1-A -10apregnadiene-3,20-dione 242. 16a,17a-isopropylidenedioxy-6,8-methy1-19- ethyl-A -10a-pregnadiene-3,20-dione 243. 6fi-methyl-19-ethy1-A -10u-pregnadien-l7uol-3,20-dione 244. 6B,16a-dimethy1-19-ethy1-A -10apregnadien-17a-o13,20-dione 245. 613,16,8-dimethy1-19-ethyl-A -10apregnadien-l7a-ol-3,20-dione Example XXII The compounds Nos. 190 to 203, inclusive, were treated in accordance with Example XX, thus afiording respectively:

Cpd. No.:

246. 19-methy1-A -1Oaregnatriene-3,20-dione 247. 16a,19-dimethyl-A -IOa-pregnatIiene- 3,20-dione 248. 16B,19-dimethyl-A -IOu-pregnatIiene- 3,20-dione 249. 16a,17u-isopropy1idenedioxy-19-methy1- A -10a-pregnatriene-3,2O-dione Cpd. No.:

250. 19-rnethy1-A -1Oaregnatrien-I7a-o1-3,20-

dione 25 1. 16a,19-dimethyl-A -10a-pregnatrien-17aol-3,20-dione 252. 16B,19-dirnethy1-A -IOa-pregnatrien-Uaol-3,20-dione 253. 19-ethy1-A -1Oa-pregnatriene-3,20-dione 254. 16a-methy1-19-ethy1-A -IOa-pregnatriene- 3,20-dione 255 16fl-methyl-19-ethyl-A -IOaregnatriene- 3,20-di0ne 25 6. 16a,17a-is0propylidenedioxy-19-ethyl-A 10a-pregnatriene-3,20-dione 257. 19-ethyl-A -IOa-pregnatrien-17a-ol-3,20-

dione 258. 16a-rnethyl-19-ethyl-A -10a-pregnatrien- 17a-ol-3,20-dione 259. 16fl-methy1-19ethy1-A -IOaregnatrien- 17a-ol-3,20-dione Example XXIII The compounds Nos. 106 to 147, inclusive, and Nos. 162 to 189, inclusive, were treated in accordance with Example XX, to produce the corresponding A -pregnadiene derivatives.

Example XXIV 1 g. of 16a,17a-isopropy1idenedioxy-19-methyl-A -10apregnene-3,20-dione (Cpd. No. 67) was heated on the steam bath with 20 cc. of 60% formic acid for 1 hour, cooled, diluted with water and the precipitate was collected, washed with water, dried, and recrystallized from acetone-hexane, thus affording 19-rnethylA -10a-pregmeme-16a,l7a-diol-3,20-dione =(Cpd. No. 260).

The compounds Nos. 74, 109, 116, 123, 130, 137, 144, 193, 200, 207, .214, 221, 228, 249 and 256 were treated following exactly the same procedure, thus yielding respectively:

Cpd. No.:

261. 19-ethyl-A -IOa-pregnene-l6a,17a-diol-3,20-

dione 262. 6a,19-dimethyl-A -IOa-pregnene-16a,17a-dio1- 3,20-dione 263. 6a-methyl-19-ethyl-A -10a-pregnene-16a,

17a-diol-3,20-dione 264. 6a-chloro-19-methyl-A -10a-pregnene-16a,

17a-diol-3,20-dione 265. 6u-chloro-19-ethyl-A -10a-pregnene-16a,17a-

dio1-3,20-dione 267. 6a-fiuoro-19-ethyl-A -10a-pregnene-16a,17a-

diol-3,20-dione 268. 19-methyl-A -10a-pregnadiene-16a,17a-

diol-3,20-dione 269. l9-ethyl-A -lOa-pregnadiene-IGa,17a-diol- 3,20-dione 270. 6-chloro-19-methyl-A -1Oa-pregnadiene-16a,

17a-diol-3,20-dione 271. 6-chloro-19-ethyl-A -10a-pregnadiene-16a,

17oc-'diOl-3,20-di0l16 272. 19-methyl-A -IOa-pregnadiene-16a,17a-

diol-3,20-dione 273. 19-ethyl-A -IOa-pregnadiene-l6a,17a-diol- 3,20-dione 274. I9-methyI-A -10a-pregnatriene-16a,17a-

diol-3,20-dione 275. 19-ethyl-A -10a-pregnatriene-160:,17m-

dio1-3,20-dione Example XXV A mixture of 1 g. of 19-methyl-A -IOaregnene-16a, 17u-dio1-3,20-dione (Cpd. No. 260), 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 19-methy1-A -pregnene- 16a,17a-diol-3,20-dione 16-acetate (Cpd. No. 276).

By the same method, the compounds Nos. 261 to 275, inclusive, were respectively converted into:

Cpd. No.:

277. 19-ethyl-A -10a-pregnene-16a,17a-di0l-3,20-

dione 16-acetate 278. 6a,19-dimethyl-A -1Oa-pregnene-16u,17a-

diol-3,20-dione 16-acetate 279. Got-methyl-19-ethyl-A -10a-pregnene-16a,17a-

diol-3,20-dione 16-acetate 280. 6wchloro-19-methyl-A -10a-pregnene-16a,

17a-diol-3,20-dione 16-acetate 281. 6a-chloro-19-ethy1-A -lOwpregnene-l6a,17a-

-diol-3,20-dine 16-acetate 282. 6a-fiuoro-19-methyl-A -IOa-pregnene-16oz,

17u-diol-3,20-dione 16-acetate 283. 6a-fluoro-19-ethyl-A -10a-pregnene-160,17a-

diol-3,20-dione 16-acetate 284. 19-methyl-A -10a-pregnadiene-16a,17a-di0l- 3,20-dione 16-acetate 285. 19-ethyl-A -IOaregnadiene-16a,17a-diol- 3,20-di0ne 16-acetate 286. 6-chloro-19-methyl-A -10a-pregnadiene-16a,

170L-diO1-3,20-dl011 16-acetate 287. 6-chloro-l9-ethy1-A -10a-pregnadiene-16ot,

17a-diol-3,20-dione 16-acetate 288. 19-methyl-A -10a-pregnadiene-16ot,17a diol- 3,20-dione 16-acetate 289. 19-ethyl-A -IOa-pregnadiene 16u,17a diol- 3,20-dione 16-acetate 290. 19-methyl-A -1Oa-pregnatriene-16a,17a-

diol-3,20-dione 16-acetate 291. 19-ethy1-A -10a-pregnatriene 16a,17 x-diol- 3,20-dione 16-acetate Example XXVI To a solution of g. of 19-methyl-A -a-pregnen-17aol-3,20-dione (Cpd. No. 68) in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and 10 cc. of caproic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to efiect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from ether-hexane produced 19-methyl A 10u-pregnen-17a-ol3,20-dione caproate (Cpd. No. 292).

The compounds Nos. 69, 70, 75, 76, and 77 were treated according to the above method, thus giving respectively:

Cpd. No.:

293. 16a,19-dirnethyl-A -10a-pregnen-17a-o1-3,20-

dione caproate 294. 16,8,l9 dimethylA -10a-pregnen-17a-ol-3,20-

dione caproate 295. 19-ethyl-A -10a-pregnen-17a-0l-3,20-dione caproate 296. 16a-methyl-19a-ethyl-A -10a-pregnen-17ot-0l- 3,20 dione caproate 297. 16,8-methyl-19-ethyl-A -1Oa-pregnen-17a-ol- 3,20-dione caproate Example XXVII The compounds Nos. 110, 111, 112, 117, 118 and 119 were treated in accordance with the procedure described in Example XXVI, thus furnishing respectively:

Cpd. No.:

298. 6a,19-dimethy1-A -10a-pregnen-17oz-ol-3,20-

dione caproate 299. 6a,16a,19-trimethyl-A -10a-pregnen-17a-ol- 3,20-dione caproate 300. 6a,16,6,19-trimethy1-A -10a-pregnen-17a-ol- 3,20-dione caproate 301. 6a-methyl-19-ethyl-A -IOa-pregnen-1704-01- 3,20-di0ne caproate 302. 6a,16a-dimethyl-19-ethyl-A -1Oa-pregnen-Uaol-3,20-dione caproate 303. 6a,IGB-dimethyl-19-ethyl-A -10a-pregnen-17ao1-3,20-dione caproate Example XX VIII The compounds Nos. 124, 125, 126, 131, 132 and 133 were treated according to Example XXVI, thus affording respectively:

Cpd. No.:

304. Got-chloro-19-methyl-A -10a-pregnen-17oc-ol- 3,20-di0ne caproate 305. Gut-chloro-16a,19-dimethyl-A -10a-pregnen- 17ot-o1-3,20-dione caproate 306. 6a-chloro-l6 3,19-dirnethyl-A -IOq-pregnen- 17a-O1-3,20-di0116 caproate 307. 6u-chlor0-19-ethyl-A -10a-pregnen-17a-ol- 3,20-di0ne caproate 308. 6a-chloro-16a-methyl-19-ethyl-A -1O-pregnen-17a-ol-3,20-dione caproate 309. 6a-chloro-16fl-methyl-19-e-t-hyl-A -10a-pregnen- 17oc-01-3,20-di0I1 caproate Example XXIX The compounds Nos. 138, 139, 140, 145, 146 and 147 were treated according to Example XXVI, thus alfo r ding respectively:

Cpd. No.:

310. 6a-fluoro-19-methy1-A -IOa-pregnen-l7a-o1- 3,20-dione caproate 311. a-fluoro-l6a,19-dimethyl-A -lOa-pregnen- 17a-ol-3,20-dione caproate 312. 6a-fluoro-16,6,19-dimethy1-A -Illa-pregnen- 17a-o1-3,20-dione caproate 313. 6u-fll101'0- 19l-ethyl-A -1 0apregnen-17a-ol- 3,20-dione caproate 314. 6a-fluoro-16a-methy1-19-ethy1-A -10u-pregnen- 17a-ol-3,20-dione caproate 315. 6a-fluoro-16fl-methyl-19-ethyl-A -10a-pregnen- 17a-0l-3,20-di011e caproate Example XXX The compounds Nos. 194, 195, 196, 201, 202 and 203 were treated following the procedure of Example XXVI, thus affording respectively:

Cpd. No.:

316. 19-methyl-A -lfla-pregnadien-17a-01-3,20-

dione caproate 317. 16a,19-dimethyl-A -10a-pregnadien?17a-ol,

3,20-di0ne caproate 318. 16B,19-dimethy1-A -10a-pregnadien-17a-01- 3,20-dione caproate 319. 19-ethyl-A -1Oa-pregnadien-17a-o1-3,20- dione caproate I 320. 16a-methyl-19 ethy1-A -10a-pregnadien-17aol-3,20-dione caproate 321. 16 8-methyl-l9-ethyl-A -10a-pregnadien-17aol-3,20-dione caproate 19 Example XXXI The compounds Nos. 222, 223, 224, 229, 230 and 231 were treated following the procedure of Example XXVI, thus affording respectively:

Example XXXI] Following the procedure described in Example XXVI, the compounds Nos. 250, 251, 252, 257, 258 and 259 were respectively converted into:

Cpd. No.:

328. 19-methyl-A IOa-Prcgnatrienl7a-ol-3 ,20-

dione caproate 329. 16a,19-dimethyl-A -lOot-pregnatrien-l7ot-ol- 3,20 dione caproate 330. 165,19-dimethyl-A -10ot-pregnatrien-17aol-3,20-dione caproate 331. 19-ethylA -10ot-pregnatrien-17 -o1-3,20-

dione caproate 332. 1Got-methyl-19-ethyl-A -lOaregnatrienl7a-o1-3,20-dione caproate 333. 16B-methyl-19-ethyl-A IOa-pregnatrien- 17oc-0l-3,20-di0116 caproate Example XXXIII The starting compounds of Example XXV were treated following the procedure described in that example except that acetic anhydride was substituted by caproic anhydride, enanthic anhydride and undecenoic anhydride thus affording the corresponding 16-caproates, l'6-enanthates and 16- undecenoates of said starting compounds.

Example XXXI V The compounds Nos. 276 to 291, inclusive, were treated in accordance with Example XXVI, thus yielding the corresponding 16-acetate-17-caproates.

Example XXX V The starting compounds of Examples XXVI, XXVII, XXVIII, XXIX, XTPQC, XXXI and XXXII were treated in accordance with Example XXVI, but using acetic anhydride and enanthic anhydride instead of caproic anhydride thus afiording the corresponding acetates and enanthates.

Example XXXVI A solution of 500 mg. of 19-methyl-A -IOu-pregnene- 16u,17a-dio1-3,20-dione (Cpd. No. 260), in 20 cc. of chloroform was treated with 1 g. of acetaldehyde and a few drops of 3 N perchloric acid and stirred at room temperature for 2 hours. After diluting with water the chloroform layer was separated, washed with aqueous saturated sodium bicarbonate solution and then with water, the chloroform was distilled and the residue was purified by chromatography on neutral alumina, thus yielding 160:,17a-ethylidenedioxy19-methyl-A -10a-pregnene-3,20-dione (Cpd. N0. 334).

The compounds Nos. 261 to 275, inclusive, were treated according to the above procedure, thus giving the corresponding 16a,17a-ethylidenedioxy compounds.

20 Example XXXVI] A mixture of 1 g. of compound No. 260, 50 cc. of freshly distilled acetophenone and 0.5 cc. of 72% perchloric acid was stirred at room temperature for 1 hour. The resulting mixture was washed with sodium bicarbonate solution and with water to neutrality, then it was steam distilled and the product extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane yielded l9-methyl-A -l0a-pregnene-16a, 17u-diol-3,20-dione 16,17-acetophenonide (Cpd. No. 335).

The compounds Nos. 261 to 275, inclusive, were treated according to the above procedure, thus yielding the corresponding 16,17-acetophenonides.

Example XXX VIII Into a solution of 3 g. of compound No. 176 in cc. of glacial acetic acid was passed a slow stream of dry hydrochloric acid for 4 hours, while maintaining the temperature around 15 C. The mixture was then poured into ice-water, the precipitate collected, washed with water, dried and recrystallized from acetone-hexane to give a compound identical with compound No. 134.

I claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms, T is a member of the group consisting of hydrogen, a-hydroxyl, (it-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms, a-methyl and fl-methyl; T and R together represent the group wherein R and R are selected from the group consisting of hydrogen and a lower hydrocarbon residue of up to 8 carbon atoms; X is lower alkyl; Z is a member of the group consisting of hydrogen, a-methyl, e-methyl, a-fiuorine, B-fiuorine, a-chlorine and fi-chlorine; and W is selected from the group consisting of a saturated linkage and a double bond between C1 and 0-2.

2. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms, T is a member of the group consisting of hydrogen, a-hydroxyl, (it-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms, vz-methyl and B-methyl; T and R together represent the group ...0 /R )a O R wherein R and R are selected from the group consisting of hydrogen and a lower hydrocarbon residue of up to 8 carbon atoms; X is lower alkyl; Z is a member of the group consisting of hydrogen, methyl, fluorine and chlorine; and W is selected from the group consisting of a saturated linkage and a double bond, between C-1 and C-2.

3. 19-methyl-A -10a-pregnene-3,20-dione.

4. 16a,19-dirnethyl-A -10a-pregnene3,20-dione 5. 16 8,19-dimethyl-A -la-pregnene-3,20-dione.

6. 16oc,17oc isopropylidenedioxy 19 methyl A -10apregnene-3,20-dione.

7. 19-methyl-A LOa-Pregnen-17x-ol-3,20-dione.

8. 16a,19-dimethy1-A -1Oa-pIegnen-17a-ol-3,20-dione.

9. 165,19-dimethy1-A -1Ou-pregnen-17oc-ol-3,20-dione.

10. 19-ethy1-A -10a-pregnene-3,2O-dione.

11. 16a-methyl-19-ethyl-A -10a-pregnene-3,20-dione.

12. 16B-methyl-19-ethyl-A -l0a-pregnene-3,20-dione.

13. 16u,17oc isopropylidenedioxy 19 ethyl-A 400;- pregnene-3,20-dione.

14. 19-ethyl-A -1Oaregnen-17u-ol-3,20-dione.

15. 16a methyl 19 ethyl-A -10a-pregnen-17u-o1- 3,20-dione.

16. methyl 19 ethyl-A -l0a-pregnen-17a-ol- 3,20,dione.

17. 6B,l9-dimethyl-A -10a-pregnene-3,20-dione.

18. 6a,l9-dirnethyl-A -10ot-pregnene-3,20-dione.

19. 6a-chloro-19-methyl-A -l0a-pregnene-3,20-dione.

20. 6a-fluoro-19-methyl-A -10a-pregnene-3,20-dione.

References Cited by the Examiner C. Chen, Tetrahedron 3, pages 43-48 (1958).

Castells et al.: J. Chem. Soc., pages 2627-2639 (1960).

Mayor et al.: J. Chem. Soc., pages 2792-2800 (1960).

Mayor et al.: J. Chem. Soc., .pages 2800-2802 (1960).

Rappoldt et al.: Recueil des Travaux Chimiques des Pays-Bas, January (1961), pages 43-46.

Westerhof et al.: Recueil des Travaux Chimiques des Pays-Bas, September (1961), pages 1048-56.

LEWIS GOTTS, Primary Examiner. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 